Age-related macular degeneration (AMD) is the leading cause of irreversible legal blindness in people over 60 years of age in the US, with over 1.8 million Americans affected by advanced disease. There is no proven effective therapy for the advanced atrophic form of the disease. Also, despite the recent advent of anti- vascular endothelial growth factor agents, the clinical outcomes for wet AMD remain suboptimal. The impact on quality of life is severe, often leading to drastic changes in life-style and significant anxiety and depression. Recent evidence suggests that chronic inflammation, likely directed towards subretinal debris generated from oxidative damage, may be important in the disease process. Genetic studies have consistently shown that a variant in complement factor H (Cfh), an important regulator of complement activation, is a strong risk factor for AMD. However, the mechanism by which Cfh is associated to the disease process is not well understood. We have recently generated chimeric Cfh transgenic mouse lines that model the Cfh variants associated to AMD. These mice develop findings consistent with early AMD. They also have a propensity to accumulate subretinal macrophages in the posterior pole. This last finding is intriguing, since some studies suggest that macrophages may be protective against AMD, while others imply that they promote disease progression. In this proposal we plan to use the Cfh transgenic mice to address three issues: 1. the role of the Cfh variants in regulating inflammation after different acute vs. chronic inflammatory stimuli, 2. determine which molecular interactions are affected by the Cfh variant (interactions of Cfh with c-reactive protein, or with glycosaminoglycans, or with other Cfh molecules), and how this effect may be relevant to AMD, and 3. determine the role of macrophages in the pathogenesis of AMD, and how that is affected by the Cfh variants. At the end of the study we hope to have a better understanding of the early pathogenesis of AMD, to have identified potential new therapeutic targets for early intervention, and to have generated a more robust animal model for the disease. PUBLIC HEALTH RELEVANCE: A variant in complement factor H significantly increases the risk for age-related macular degeneration (AMD), a very prevalent blinding disorder. Our goal in this proposal is to understand how Cfh variants are involved in the early mechanisms of disease in AMD. We hope to use this information to identify new targets for early therapeutic intervention, in order to modify the disease course before irreversible vision loss has occurred.